Abstract

BACKGROUND:

Loss-of-function mutations in the gene KCNQ1 encoding the Kv7.1 K(+) channel cause long QT syndrome type 1 (LQT1), whereas gain-of-function mutations are associated with short QT syndrome as well as familial atrial fibrillation (FAF). However, KCNQ1 mutation pleiotropy, which is capable of expressing both LQT1 and FAF, has not been demonstrated for a discrete KCNQ1 mutation. The genotype-phenotype relationship for a family with FAF suggests a possible association with the LQT1 p.Arg231Cys-KCNQ1 (R231C-Q1) mutation.

OBJECTIVE:

The purpose of this study was to determine whether R231C-Q1 also can be linked to FAF.

METHODS:

The R231C-Q1 proband with AF underwent genetic testing for possible mutations in 10 other AF-linked genes plus KCNH2 and SCN5A. Sixteen members from five other R231C-positive LQT1 families were genetically tested for 21 single nucleotide polymorphisms (SNPs) to determine if the FAF family had discriminatory SNPs associated with AF. R231C-Q1 was expressed with KCNE1 (E1) in HEK293 cells, and Q1E1 currents (I(Q1E1)) were analyzed using the whole-cell patch-clamp technique.

CONCLUSION:

Constitutively active I(Q1E1) and a smaller peak I(Q1E1) are common features of FAF-associated and LQT1-associated mutations, respectively. These data suggest that the mixed functional properties of R231C-Q1 may predispose some families to LQT1 or FAF. We conclude that R231C is a pleiotropic missense mutation capable of LQT1 expression, AF expression, or both.

Pedigrees of the six families carrying R231C-Q1. Males and females are represented as squares and circles, respectively. The different generations are denoted using roman numerals, and each individual in a generation is numbered. The genotype/phenotypes are defined in the key.

A: Representative families of whole-cell currents recorded from cells transfected with E1 and WT-Q1 DNA (WT, ■) or WT-Q1 and R231C-Q1 DNA (WT & R231C, ▲). The currents were measured by applying step pulses from −120 to −10 mV for 50 ms, followed by a tail pulse to −50 mV for 150 ms. The corresponding mean peak step (B) and tail currents (C) are plotted as a function of step voltage. D: Ventricular action potential waveform and corresponding averaged current traces measured at 37°C from nontransfected (HEK) cells and cells transfected with E1 and WT-Q1 DNA or WT-Q1 and R231C-Q1 DNA.

A, left: Structural model of Q1 in the closed state from the “extracellular” side looking into the pore. The backbone of each individual Q1 α-subunit is shown as a different colored ribbon. The space filled atoms for the S140 (pink), E160 (purple), and R231 (orange) residues are shown in each α-subunit. Right:Red α-subunit magnified. The side chains of S140 and E160 are predicted to be close enough to form van der Waals contacts with R231 in the closed state. B: Computational model of a human atrial action potential (AP) waveform pulsed at 1 Hz with the corresponding IKs and channel open probability. Blue traces represent control conditions. Red traces show a modification of the model that included a reduction in the number of functional channels by ~50% and a small constitutively active IKs. C: Computational model of a human ventricular AP pulsed at 1 Hz with the corresponding IKs and channel open probability. Blue traces represent control conditions. Red traces show a modification of the model that included the same reduction in functional channels and constitutively active IKs as shown in panel B.